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1.
Mol Pharm ; 16(1): 462-467, 2019 01 07.
Artigo em Inglês | MEDLINE | ID: mdl-30495960

RESUMO

Low molecular weight nucleoside gelators hold great promise in drug delivery and particularly for the delivery of biologics because of their excellent biocompatibility. However, the influence of these gelators on protein aggregation inhibition has not yet been studied. Protein aggregation is the most significant cause of protein instability and can severely impact the biological activity of the protein, impairing the quality and safety of the formulation. Herein, we report the ability of a nucleoside-based gelator, N4-octanoyl-2'-deoxycytidine, to inhibit protein aggregation. Using turbidimetric, spectroscopic, and microscopic methods, we demonstrate that protein aggregation inhibition is dependent on gelator concentration. Moreover, we have found that the protein is still functionally active in the hydrogel.


Assuntos
Nucleosídeos/química , Sistemas de Liberação de Medicamentos , Interações Hidrofóbicas e Hidrofílicas , Peso Molecular , Agregados Proteicos
3.
Langmuir ; 34(50): 15109-15125, 2018 12 18.
Artigo em Inglês | MEDLINE | ID: mdl-30032622

RESUMO

Among the many parameters that have been explored to exercise control over self-assembly processes, the influence of surface properties on self-assembly has been recognized as important but has received considerably less attention than other factors. This is particularly true for biomolecule-derived self-assembling molecules such as protein, peptide, and nucleobase derivatives. Because of their relevance to biomaterial and drug delivery applications, interest in these materials is increasing. As the formation of supramolecular structures from these biomolecule derivatives inevitably brings them into contact with the surfaces of surrounding materials, understanding and controlling the impact of the properties of these surfaces on the self-assembly process are important. In this feature article, we present an overview of the different surface parameters that have been used and studied for the direction of the self-assembly of protein, peptide, and nucleoside-based molecules. The current mechanistic understanding of these processes will be discussed, and potential applications of surface-mediated self-assembly will be outlined.


Assuntos
Nucleosídeos/química , Peptídeos/química , Proteínas/química , Substâncias Macromoleculares/síntese química , Substâncias Macromoleculares/química , Tamanho da Partícula , Propriedades de Superfície
4.
Langmuir ; 34(23): 6912-6921, 2018 06 12.
Artigo em Inglês | MEDLINE | ID: mdl-29757652

RESUMO

Among the diversity of existing supramolecular hydrogels, nucleic acid-based hydrogels are of particular interest for potential drug delivery and tissue engineering applications because of their inherent biocompatibility. Hydrogel performance is directly related to the nanostructure and the self-assembly mechanism of the material, an aspect that is not well-understood for nucleic acid-based hydrogels in general and has not yet been explored for cytosine-based hydrogels in particular. Herein, we use a broad range of experimental characterization techniques along with molecular dynamics (MD) simulation to demonstrate the complementarity and applicability of both approaches for nucleic acid-based gelators in general and propose the self-assembly mechanism for a novel supramolecular gelator, N4-octanoyl-2'-deoxycytidine. The experimental data and the MD simulation are in complete agreement with each other and demonstrate the formation of a hydrophobic core within the fibrillar structures of these mainly water-containing materials. The characterization of the distinct duality of environments in this cytidine-based gel will form the basis for further encapsulation of both small hydrophobic drugs and biopharmaceuticals (proteins and nucleic acids) for drug delivery and tissue engineering applications.


Assuntos
Sistemas de Liberação de Medicamentos/métodos , Hidrogéis/síntese química , Simulação de Dinâmica Molecular , Engenharia Tecidual/métodos , Hidrogéis/química , Interações Hidrofóbicas e Hidrofílicas
5.
Soft Matter ; 14(48): 9851-9855, 2018 Dec 12.
Artigo em Inglês | MEDLINE | ID: mdl-30506072

RESUMO

Surface-mediated self-assembly has potential in biomaterial development but underlying rules governing surface-gelator interactions are poorly understood. Here, we correlate surface properties with structural characterization data of nucleoside-based gels obtained by GISAXS and GIWAXS and find that hydrophobicity descriptors (log P, polar surface area, aromaticity) are key predictors for the gel structures formed.

7.
Langmuir ; 30(41): 12429-37, 2014 Oct 21.
Artigo em Inglês | MEDLINE | ID: mdl-25259412

RESUMO

We demonstrate the nonaqueous self-assembly of a low-molecular-mass organic gelator based on an electroactive p-type tetrathiafulvalene (TTF)-dipeptide bioconjugate. We show that a TTF moiety appended with diphenylalanine amide derivative (TTF-FF-NH2) self-assembles into one-dimensional nanofibers that further lead to the formation of self-supporting organogels in chloroform and ethyl acetate. Upon doping of the gels with electron acceptors (TCNQ/iodine vapor), stable two-component charge transfer gels are produced in chloroform and ethyl acetate. These gels are characterized by various spectroscopy (UV-vis-NIR, FTIR, and CD), microscopy (AFM and TEM), rheology, and cyclic voltammetry techniques. Furthermore, conductivity measurements performed on TTF-FF-NH2 xerogel nanofiber networks formed between gold electrodes on a glass surface indicate that these nanofibers show a remarkable enhancement in the conductivity after doping with TCNQ.


Assuntos
Dipeptídeos/química , Géis/síntese química , Compostos Heterocíclicos/química , Nanofibras/química , Dipeptídeos/síntese química , Géis/química , Estrutura Molecular
8.
Front Immunol ; 15: 1411872, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-39034997

RESUMO

During the foreign body response (FBR), macrophages fuse to form foreign body giant cells (FBGCs). Modulation of FBGC formation can prevent biomaterial degradation and loss of therapeutic efficacy. However, the microenvironmental cues that dictate FBGC formation are poorly understood with conflicting reports. Here, we identified molecular and cellular factors involved in driving FBGC formation in vitro. Macrophages demonstrated distinct fusion competencies dependent on monocyte differentiation. The transition from a proinflammatory to a reparative microenvironment, characterised by specific cytokine and growth factor programmes, accompanied FBGC formation. Toll-like receptor signalling licensed the formation of FBGCs containing more than 10 nuclei but was not essential for cell-cell fusion to occur. Moreover, the fibroblast-macrophage crosstalk influenced FBGC development, with the fibroblast secretome inducing macrophages to secrete more PDGF, which enhanced large FBGC formation. These findings advance our understanding as to how a specific and timely combination of cellular and microenvironmental factors is required for an effective FBR, with monocyte differentiation and fibroblasts being key players.


Assuntos
Diferenciação Celular , Fusão Celular , Microambiente Celular , Fibroblastos , Reação a Corpo Estranho , Células Gigantes de Corpo Estranho , Macrófagos , Macrófagos/metabolismo , Macrófagos/imunologia , Reação a Corpo Estranho/imunologia , Fibroblastos/metabolismo , Humanos , Células Gigantes de Corpo Estranho/metabolismo , Células Gigantes de Corpo Estranho/patologia , Animais , Monócitos/imunologia , Monócitos/metabolismo , Camundongos , Citocinas/metabolismo , Transdução de Sinais , Células Cultivadas
9.
RSC Sustain ; 2(9): 2559-2580, 2024 Aug 28.
Artigo em Inglês | MEDLINE | ID: mdl-39211508

RESUMO

Biocatalysis in ionic liquids enables novel routes for bioprocessing. Enzymes derived from extremophiles promise greater stability and activity under ionic liquid (IL) influence. Here, we probe the enzyme alcohol dehydrogenase 2 from the halophilic archaeon Haloferax volcanii in thirteen different ion combinations for relative activity and analyse the results against molecular dynamics (MD) simulations of the same IL systems. We probe the ionic liquid property space based on ion polarizability and molecular electrostatic potential. Using the radial distribution functions, survival probabilities and spatial distribution functions of ions, we show that cooperative ion-ion interactions determine ion-protein interactions, and specifically, strong ion-ion interactions equate to higher enzymatic activity if neither of the ions interact strongly with the protein surface. We further demonstrate a tendency for cations interacting with the protein surface to be least detrimental to enzymatic activity if they show a low polarizability when combined with small hydrophilic anions. We also find that the IL ion influence is not mitigated by the surplus of negatively charged residues of the halophilic enzyme. This is shown by free energy landscape analysis in root mean square deviation and distance variation plots of active site gating residues (Trp43 and His273) demonstrating no protection of specific structural elements relevant to preserving enzymatic activity. On the other hand, we observe a general effect across all IL systems that a tight binding of water at acidic residues is preferentially interrupted at these residues through the increased presence of potassium ions. Overall, this study demonstrates a co-ion interaction dependent influence on allosteric surface residues controlling the active/inactive conformation of halophilic alcohol dehydrogenase 2 and the necessity to engineer ionic liquid systems for enzymes that rely on the integrity of functional surface residues regardless of their halophilicity or thermophilicity for use in bioprocessing.

10.
Biomacromolecules ; 14(12): 4368-76, 2013 Dec 09.
Artigo em Inglês | MEDLINE | ID: mdl-24256076

RESUMO

Molecular self-assembly provides a versatile route for the production of nanoscale materials for medical and technological applications. Herein, we demonstrate that the cooperative self-assembly of amphiphilic small molecules and proteins can have drastic effects on supramolecular nanostructuring of resulting materials. We report that mesoscale, fractal-like clusters of proteins form at concentrations that are orders of magnitude lower compared to those usually associated with molecular crowding at room temperature. These protein clusters have pronounced effects on the molecular self-assembly of aromatic peptide amphiphiles (fluorenylmethoxycarbonyl- dipeptides), resulting in a reversal of chiral organization and enhanced order through templating and binding. Moreover, the morphological and mechanical properties of the resultant nanostructured gels can be controlled by the cooperative self-assembly of peptides and protein fractal clusters, having implications for biomedical applications where proteins and peptides are both present. In addition, fundamental insights into cooperative interplay of molecular interactions and confinement by clusters of chiral macromolecules is relevant to gaining understanding of the molecular mechanisms of relevance to the origin of life and development of synthetic mimics of living systems.


Assuntos
Dipeptídeos/química , Hidrogéis/química , Lactoglobulinas/química , Soroalbumina Bovina/química , Aminoácidos/química , Animais , Bovinos , Dicroísmo Circular , Módulo de Elasticidade , Fluorenos/química , Microscopia de Força Atômica , Multimerização Proteica , Estrutura Secundária de Proteína , Estereoisomerismo
11.
Surf Interface Anal ; 54(9): 986-1007, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-38617442

RESUMO

Interpretation of X-ray photoelectron spectroscopy (XPS) spectra of complex material surfaces, such as those obtained after surface plasma treatment of polymers, is confined by the available references. The limited understanding of the chemical surface composition may impact the ability to determine suitable coupling chemistries used for surface decoration or assess surface-related properties like biocompatibility. In this work, XPS is used to investigate the chemical composition of various ultra-high-molecular-weight polyethylene (UHMWPE) surfaces. UHMWPE doped with α-tocopherol or functionalised by active screen plasma nitriding (ASPN) was investigated as a model system. Subsequently, a more complex combined system obtained by ASPN treatment of α-tocopherol doped UHMWPE was investigated. Through ab initio orbital calculations and by employing Koopmans' theorem, the core-electron binding energies (CEBEs) were evaluated for a substantial number of possible chemical functionalities positioned on PE-based model structures. The calculated ΔCEBEs showed to be in reasonable agreement with experimental reference data. The calculated ΔCEBEs were used to develop a material-specific peak model suitable for the interpretation of merged high-resolution C 1 s, N 1 s and O 1 s XPS spectra of PE-based materials. In contrast to conventional peak fitting, the presented approach allowed the distinction of functionality positioning (i.e. centred or end-chain) and evaluation of the long-range effects of the chemical functionalities on the PE carbon backbone. Altogether, a more detailed interpretation of the modified UHMWPE surfaces was achieved whilst reducing the need for manual input and personal bias introduced by the spectral analyst.

12.
RSC Adv ; 12(26): 16561-16569, 2022 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-35754913

RESUMO

Control over intracellular release of therapeutic compounds incorporated into nano-carriers will open new possibilities for targeted treatments of various diseases including cancer, and viral and bacterial infections. Here we report our study on mechanoresponsive nano-sized liposomes which, following internalization by cells, achieve intracellular delivery of encapsulated cargo on application of external ultrasound stimulus. This is demonstrated in a bespoke cell reporter system designed to assess free drug in cytoplasm. Biophysical analyses show that drug release is attributable to the action of a mechanoresponsive spiropyran-based compound embedded in the liposomal lipid membrane. Exposure to external ultrasound stimulus results in opening of the molecular structure of the embedded spiropyran, a consequent increase in liposomal lipid membrane fluidity, and size-dependent release of encapsulated model drugs, all pointing to lipid bilayer perturbation. The study hence illustrates feasibility of the proposed concept where intracellular drug release from mechanoresponsive liposomes can be triggered on demand by external ultrasound stimulus.

13.
Sci Rep ; 12(1): 8165, 2022 05 17.
Artigo em Inglês | MEDLINE | ID: mdl-35581256

RESUMO

Skeletal stem cells (SSCs, or mesenchymal stromal cells typically referred to as mesenchymal stem cells from the bone marrow) are a dynamic progenitor population that can enter quiescence, self-renew or differentiate depending on regenerative demand and cues from their niche environment. However, ex vivo, in culture, they are grown typically on hard polystyrene surfaces, and this leads to rapid loss of the SSC phenotype. While materials are being developed that can control SSC growth and differentiation, very few examples of dynamic interfaces that reflect the plastic nature of the stem cells have, to date, been developed. Achieving such interfaces is challenging because of competing needs: growing SSCs require lower cell adhesion and intracellular tension while differentiation to, for example, bone-forming osteoblasts requires increased adhesion and intracellular tension. We previously reported a dynamic interface where the cell adhesion tripeptide arginine-glycine-aspartic acid (RGD) was presented to the cells upon activation by user-added elastase that cleaved a bulky blocking group hiding RGD from the cells. This allowed for a growth phase while the blocking group was in place and the cells could only form smaller adhesions, followed by an osteoblast differentiation phase that was induced after elastase was added which triggered exposure of RGD and subsequent cell adhesion and contraction. Here, we aimed to develop an autonomous system where the surface is activated according to the need of the cell by using matrix metalloprotease (MMP) cleavable peptide sequences to remove the blocking group with the hypothesis that the SSCs would produce higher levels of MMP as the cells reached confluence. The current studies demonstrate that SSCs produce active MMP-2 that can cleave functional groups on a surface. We also demonstrate that SSCs can grow on the uncleaved surface and, with time, produce osteogenic marker proteins on the MMP-responsive surface. These studies demonstrate the concept for cell-controlled surfaces that can modulate adhesion and phenotype with significant implications for stem cell phenotype modulation.


Assuntos
Osteogênese , Células-Tronco , Diferenciação Celular , Células Cultivadas , Oligopeptídeos/farmacologia , Osteogênese/fisiologia , Elastase Pancreática
14.
Int J Pharm ; 622: 121828, 2022 Jun 25.
Artigo em Inglês | MEDLINE | ID: mdl-35595041

RESUMO

Intraperitoneal (IP) drug delivery of chemotherapeutic agents, administered through hyperthermal intraperitoneal chemotherapy (HIPEC) and pressurized intraperitoneal aerosolized chemotherapy (PIPAC), is effective for the treatment of peritoneal malignancies. However, these therapeutic interventions are cumbersome in terms of surgical practice and are often associated with the formation of peritoneal adhesions, due to the catheters inserted into the peritoneal cavity during these procedures. Hence, there is a need for the development of drug delivery systems that can be administered into the peritoneal cavity. In this study, we have developed a nanocapsule (NCs)-loaded hydrogel for drug delivery in the peritoneal cavity. The hydrogel has been developed using poly(ethylene glycol) (PEG) and thiol-maleimide chemistry. NCs-loaded hydrogels were characterized by rheology and their resistance to dilution and drug release were determined in vitro. Using IVIS® to measure individual organ and recovered gel fluorescence intensity, an in vivo imaging study was performed and demonstrated that NCs incorporated in the PEG gel were retained in the IP cavity for 24 h after IP administration. NCs-loaded PEG gels could find potential applications as biodegradable, drug delivery systems that could be implanted in the IP cavity, for example at a the tumour resection site to prevent recurrence of microscopic tumours.


Assuntos
Nanocápsulas , Neoplasias Peritoneais , Sistemas de Liberação de Medicamentos , Humanos , Hidrogéis/química , Injeções Intraperitoneais
15.
Chem Soc Rev ; 39(9): 3351-7, 2010 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-20676412

RESUMO

With improved understanding of the design rules for self-assembling peptides, new challenges will be faced to incorporate these materials into dynamic systems of higher complexity and functionality. In this highlight article we discuss very recent advances in these areas. Three areas are covered: (i) molecular networks based on peptides and their interactions including (bio-) catalytically driven systems; (ii) supramolecular functionality, both in the context of biological and nanotechnology applications; (iii) approaches to effectively interface peptides with synthetic and biological materials. We also discuss challenges and opportunities for the design of a new generation of peptide nanomaterials for the next decade.


Assuntos
Substâncias Macromoleculares/química , Substâncias Macromoleculares/uso terapêutico , Nanoestruturas/química , Nanotecnologia/métodos , Neoplasias/terapia , Fragmentos de Peptídeos/química , Animais , Humanos , Fragmentos de Peptídeos/metabolismo , Conformação Proteica
16.
Mater Sci Eng C Mater Biol Appl ; 121: 111852, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33579486

RESUMO

Polymeric, biodegradable, microspheres (MS) presenting a biomimetic surface of extracellular matrix (ECM) proteins are currently used for transporting cells and/or encapsulated proteins for regenerative medicine studies. They can be made of (lactic-co-glycolic acid) (PLGA) or of a more hydrophilic PLGA-P188 (Poloxamer188)-PLGA polymer allowing for the complete release of the therapeutic proteins. They promote stem cell adhesion, cell survival and differentiation after transplantation. Although the biological effectiveness of these microcarriers is established, a detailed understanding of the protein and cell interactions with the microcarrier surface remain unclear due to a lack of information of their surface properties. The aim of this study was to characterize the physicochemical properties of two polymeric MS systems and determine the effect of laminin and poly-d-lysine coated microcarriers on stem cell adhesion, survival and neuronal differentiation. The hydrophobicity and topography of PLGA MS promoted protein adsorption and the stem cells quickly adhered and spread on the surface of these microcarriers. In contrast less proteins adsorbed onto PLGA-P188-PLGA MS and although cells adhered to these microcarriers, they remained round and did not spread on their surface. Despite these early-stage differences, our results suggest that the nature of the MS does not strongly influence the long-term cell behavior. The cells exhibit the same cell number, differentiation profile and ability to secrete ECM molecules regardless of the type of microcarrier used. Likely the ECM molecules that form a microenvironment around both of these 3D microcarrier/cell constructs over time play a role in this converging cell behavior. We have thus furthered our understanding of the physicochemical properties of polymeric cell carriers affecting stem cell behavior to help tailor suitable microcarriers for neuroregenerative applications.


Assuntos
Células-Tronco Mesenquimais , Adesão Celular , Moléculas de Adesão Celular , Células Cultivadas , Ácido Láctico , Microesferas , Copolímero de Ácido Poliláctico e Ácido Poliglicólico
17.
Chem Sci ; 12(42): 14260-14269, 2021 Nov 03.
Artigo em Inglês | MEDLINE | ID: mdl-34760212

RESUMO

Controlling supramolecular self-assembly across multiple length scales to prepare gels with localised properties is challenging. Most strategies concentrate on fabricating gels with heterogeneous components, where localised properties are generated by the stimuli-responsive component. Here, as an alternative approach, we use a spiropyran-modified surface that can be patterned with light. We show that light-induced differences in surface chemistry can direct the bulk assembly of a low molecular weight gelator, 2-NapAV, meaning that mechanical gel properties can be controlled by the surface on which the gel is grown. Using grazing incidence X-ray diffraction and grazing incidence small angle X-ray scattering, we demonstrate that the origin of the different gel properties relates to differences in the architectures of the gels. This provides a new method to prepare a single domain (i.e., chemically homogeneous) hydrogel with locally controlled (i.e., mechanically heterogeneous) properties.

18.
Photochem Photobiol Sci ; 9(7): 1009-17, 2010 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-20505876

RESUMO

A molecular dyad, , has been prepared that incorporates a boron dipyrromethene (Bodipy) group functionalized at the meso position with an anthracenyl unit. Emission from the dyad contains contributions from both localized fluorescence from the Bodipy unit and exciplex-like emission associated with an intramolecular charge-transfer state. The peak position, intensity and lifetime of this exciplex emission are solvent dependent and the shift in the emission maximum shows a linear relationship to the solvent polarity function (Deltaf). The calculated dipole moment for the exciplex is 22.5 +/- 2.2 D. The radiative rate constant (k(RAD)) for exciplex emission decreases progressively with increasing solvent polarity. In this latter case, k(RAD) shows an obvious dependence on the energy gap between the exciplex state and the first-excited singlet state resident on the Bodipy unit. The emission characteristics for dissolved in perfluorooctane are used to characterize the refractive index and dielectric constant of the solvent.

19.
RSC Adv ; 10(30): 17642-17652, 2020 May 05.
Artigo em Inglês | MEDLINE | ID: mdl-35515604

RESUMO

The surface of a medical implant is required to interact favourably with ions, biomolecules and cells in vivo, commonly resulting in the formation of the extracellular matrix. Medical grade Ti6Al4V alloy is widely used in orthopaedic and dental applications for bone replacement due to its advantageous mechanical properties and biocompatibility, which enhances the adhesion between native tissue and the implanted material. In this study, chemical and thermal modification of a medical-grade Ti6Al4V alloy were performed to enhance electrostatic interactions at the alloy surface with a synthetic peptide, suitable for conferring drug release capabilities and antimicrobial properties. The modified surfaces exhibited a range of topographies and chemical compositions depending primarily on the treatment temperature. The surface wetting behaviour was found to be pH-dependent, as were the adhesive properties, evidenced by chemical force titration atomic force microscopy.

20.
Biointerphases ; 15(4): 041008, 2020 08 04.
Artigo em Inglês | MEDLINE | ID: mdl-32752604

RESUMO

Protein-coated polymer-based microparticles are attractive supports for cell delivery, but the interplay between microparticle properties, protein coating, and cell response is poorly understood. The interest in alternative microparticle formulations increases the need for a better understanding of how functional protein coatings form on different microparticles. In this work, microparticle formulations based on biodegradable polymers [poly (lactic-co-glycolic acid) (PLGA) and the triblock copolymer PLGA-poloxamer-PLGA] were prepared via an emulsion-based process. To explore the impact that the use of a surfactant has on the properties of the microparticles, the emulsion was stabilized by using either a surfactant, poly(vinyl alcohol), or an organic solvent, propylene glycol. Four different types of microparticles were prepared through combinations of the two types of polymers and the two types of stabilizers. The coating of microparticles with proteins/polypeptides such as fibronectin and poly-d-lysine has been demonstrated before and is an integral step for their application as microcarriers, e.g., for cell delivery; however, the impact of the microparticles' surface chemical properties on the formation (prevalence and distribution) of the mixed polypeptide coatings and the influence on subsequent cell attachment remain to be elucidated. Using a colocalization analysis approach on ToF-SIMS images of protein-coated microparticles, we show that the use of propyleneglycol over PVA as well as the substitution of PLGA by the triblock copolymer resulted in enhanced protein adsorption. Furthermore, if propyleneglycol is used, the substitution of PLGA with the triblock copolymer leads to increased stem cell adhesion.


Assuntos
Fibronectinas/química , Polilisina/química , Polímeros/química , Adesão Celular/efeitos dos fármacos , Técnicas de Cultura de Células/instrumentação , Técnicas de Cultura de Células/métodos , Proliferação de Células/efeitos dos fármacos , Humanos , Células-Tronco Mesenquimais/citologia , Células-Tronco Mesenquimais/metabolismo , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/química , Polímeros/farmacologia , Álcool de Polivinil/química , Propriedades de Superfície
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